Evaluating and improving the description of London dispersion interactions in molecular mechanical force fields using the exchange-hole dipole moment model

Molecular simulations are used extensively to model processes in biophysics and biochemistry. These methods approximate the intramolecular and intermolecular interactions of the molecules in the system with a set of simplified mathematical expressions. London dispersion forces account for a significant portion of intermolecular interactions. These interactions play an important role in condensed matter physics and many biophysical phenomena. In this thesis, the eXchange-hole Dipole Moment model (XDM) of density functional theory was used to evaluate the dispersion coefficients in popular molecular mechanical models that are often used for simulations of water, organic molecules, and proteins. The dispersion coefficients derived from XDM calculations were compared to those extracted from molecular mechanical models with parameters from the GAFF, CGenFF, and OPLS force fields. For the generalized force fields, 88 organic molecules were evaluated. The Amber ff14sb, OPLS-AA, and CHARMM36 protein force fields were also evaluated using side chains models. Generally, the force field molecular C₆ dispersion coefficients overestimate the XDM C₆ dispersion coefficients by 50{60%. Despite this, these models predict the solvation energies of these molecules correctly. This trend was attributed to the neglect of higher order dispersion terms. In the empirical parameterization of these force fields, the interaction energy that should arise from these higher order terms will be spuriously added to the C₆ term. In the final chapter, a water model was developed with an improved non-bonded potential that describes repulsive forces more accurately using an exponential Buckingham-type term and includes C₆ and C₈ dispersion terms. High-performance GPU-CUDA and vectorized expressions for this potential were implemented in OpenMM. The model is able to predict the structural, physical, and transport properties of liquid water accurately

Evaluating Force-Field London Dispersion Coefficients Using the Exchange-Hole Dipole Moment Model

The exchange-hole dipole moment (XDM) model from density-functional theory predicts atomic and molecular London dispersion coefficients from first principles, providing an innovative strategy to validate the dispersion terms of molecular-mechanical force fields. In this work, the XDM model was used to obtain the London dispersion coefficients of 88 organic molecules relevant to biochemistry and pharmaceutical chemistry and the values compared with those derived from the Lennard-Jones parameters of the CGenFF, GAFF, OPLS, and Drude polarizable force fields…..(see full abstract). Finally, XDM-derived dispersion coefficients were used to parameterize molecular-mechanical force fields for five liquids – benzene, toluene, cyclohexane, n-pentane, and n-hexane – which resulted in improved accuracy in the computed enthalpies of vaporization despite only having to evaluate a much smaller section of the parameter space.</p

Evaluating the London Dispersion Coefficients of Protein Force Fields Using the Exchange-Hole Dipole Moment Model

London dispersion is one of the fundamental intermolecular interactions involved in protein folding and dynamics. The popular CHARMM36, Amber ff14sb, and OPLS-AA force fields represent these interactions through the C6 /r 6 term of the Lennard-Jones potential. The C6 parameters are assigned empirically, so these parameters arenot necessarily a realistic representation of the true dispersion interactions. In this work, dispersion coefficients of all three force fields were compared to correspondingvalues from quantum-chemical calculations using the exchange-hole dipole moment (XDM) model. The force field values were found to be roughly 50% larger than the XDM values for protein backbone and side-chain models. The CHARMM36 and Amber OL15 force fields for nucleic acids were also found to exhibit this trend. To explore how these elevated dispersion coefficients affect predicted properties, the hydration energies of the side-chain models were calculated using the staged REMD-TI method of Deng and Roux for the CHARMM36, Amber ff14sb, and OPLS-AA force fields. Despite having large C 6 dispersion coefficients, these force fields predict side-chain hydration energies that are in generally good agreement with the experimental values, including for hydrocarbon residues where the dispersion component is the dominant attractive solute–solvent interaction. This suggests that these force fields predict the correct total strength of dispersion interactions, despite C6 coefficients that are considerably larger than XDM predicts. An analytical expression for the water–methane dispersion energy using XDM dispersion coefficients shows that that higher-order dispersion terms(i.e., C 8 and C 10 ) account for roughly 37.5% of the hydration energy of methane. This suggests that the C 6 dispersion coefficients used in contemporary force fields areelevated to account for the neglected higher-order terms. Force fields that include higher-order dispersion interactions could resolve this issue.</div

Evaluating Force-Field London Dispersion Coefficients Using the Exchange-Hole Dipole Moment Model

London dispersion interactions play an integral role in materials science and biophysics. Force fields for atomistic molecular simulations typically represent dispersion interactions by the 12-6 Lennard-Jones potential using empirically determined parameters. These parameters are generally underdetermined, and there is no straightforward way to test if they are physically realistic. Alternatively, the exchange-hole dipole moment (XDM) model from density-functional theory predicts atomic and molecular London dispersion coefficients from first principles, providing an innovative strategy to validate the dispersion terms of molecular-mechanical force fields. In this work, the XDM model was used to obtain the London dispersion coefficients of 88 organic molecules relevant to biochemistry and pharmaceutical chemistry and the values compared with those derived from the Lennard-Jones parameters of the CGenFF, GAFF, OPLS, and Drude polarizable force fields. The molecular dispersion coefficients for the CGenFF, GAFF, and OPLS models are systematically higher than the XDM-calculated values by a factor of roughly 1.5, likely due to neglect of higher order dispersion terms and premature truncation of the dispersion-energy summation. The XDM dispersion coefficients span a large range for some molecular-mechanical atom types, suggesting an unrecognized source of error in force-field models, which assume that atoms of the same type have the same dispersion interactions. Agreement with the XDM dispersion coefficients is even poorer for the Drude polarizable force field. Popular water models were also examined, and TIP3P was found to have dispersion coefficients similar to the experimental and XDM references, although other models employ anomalously high values. Finally, XDM-derived dispersion coefficients were used to parametrize molecular-mechanical force fields for five liquidsbenzene, toluene, cyclohexane, <i>n</i>-pentane, and <i>n</i>-hexanewhich resulted in improved accuracy in the computed enthalpies of vaporization despite only having to evaluate a much smaller section of the parameter space

Evaluating the London Dispersion Coefficients of Protein Force Fields Using the Exchange-Hole Dipole Moment Model

London dispersion is one of the fundamental interactions involved in protein folding and dynamics. The popular CHARMM36, Amber ff14sb, and OPLS-AA force fields represent these interactions through the <i>C</i>₆/<i>r</i>⁶ term of the Lennard-Jones potential, where the <i>C</i>₆ parameters are assigned empirically. Here, dispersion coefficients of these three force fields are shown to be roughly 50% larger than values calculated using the quantum mechanically derived exchange-hole dipole moment (XDM) model. The CHARMM36 and Amber OL15 force fields for nucleic acids also exhibit this trend. The hydration energies of the side-chain models were calculated using REMD-TI for the CHARMM36, Amber ff14sb, and OPLS-AA force fields. These force fields predict side-chain hydration energies that are in generally good agreement with the experimental values, which suggests that the total strength of aqueous dispersion interactions is correct, despite <i>C</i>₆ coefficients that are considerably larger than XDM predicts. An analytical expression for the dispersion hydration energy using XDM coefficients shows that higher-order dispersion terms (i.e., <i>C</i>₈ and <i>C</i>₁₀) account for roughly 37.5% of the hydration energy of methane. This suggests that the <i>C</i>₆ dispersion coefficients used in contemporary force fields are elevated to account for the neglected higher-order terms

Evaluating the London Dispersion Coefficients of Protein Force Fields Using the Exchange-Hole Dipole Moment Model

London dispersion is one of the fundamental interactions involved in protein folding and dynamics. The popular CHARMM36, Amber ff14sb, and OPLS-AA force fields represent these interactions through the <i>C</i>₆/<i>r</i>⁶ term of the Lennard-Jones potential, where the <i>C</i>₆ parameters are assigned empirically. Here, dispersion coefficients of these three force fields are shown to be roughly 50% larger than values calculated using the quantum mechanically derived exchange-hole dipole moment (XDM) model. The CHARMM36 and Amber OL15 force fields for nucleic acids also exhibit this trend. The hydration energies of the side-chain models were calculated using REMD-TI for the CHARMM36, Amber ff14sb, and OPLS-AA force fields. These force fields predict side-chain hydration energies that are in generally good agreement with the experimental values, which suggests that the total strength of aqueous dispersion interactions is correct, despite <i>C</i>₆ coefficients that are considerably larger than XDM predicts. An analytical expression for the dispersion hydration energy using XDM coefficients shows that higher-order dispersion terms (i.e., <i>C</i>₈ and <i>C</i>₁₀) account for roughly 37.5% of the hydration energy of methane. This suggests that the <i>C</i>₆ dispersion coefficients used in contemporary force fields are elevated to account for the neglected higher-order terms